Thursday, November 04, 2010

DNA for Healthy Aging, and Rebuilding the Brain After Stroke

We will look at two studies that relate to the quest for longer, healthier, more productive and fulfilling lives. First, researchers at the University of Miami looked at an Amish population and discovered that a certain genetic pattern in the mitochondria seems to allow for a much healthier lifespan into the 80s.

On Friday they will present a paper showing that 15 percent of healthy Amish octogenarians have "haplogroup X," a genetic pattern within the mitochondria, which are the regions of cells that generate energy and help guard against deterioration. Haplogroup X is generally found in only 2 percent of Europeans, from whom the Amish descended. In the University of Miami study, only 3 percent of the control group—Amish people who had made it to 80 but suffered from significant disease or disability—had the genetic variant. The paper will be featured during a session at the American Society of Human Genetics' annual meeting in Washington, D.C.

Researchers who study aging have long suspected that mitochondria play a role in aging. Mitochondria are responsible for processing metabolized food particles into adenosine triphosphate, which fuels vital cellular processes. They're also involved in cell growth and differentiation. But the ability of mitochondria to function properly seems to decline with age.

Understanding the reason for that decline—and the genes that might control it—has been challenging. Mitochondria have their own DNA, which is passed down from the mother only. This unique chromosome has variations, called haplogroups. Nine such haplogroups have been well characterized in people of European descent, Scott says. But only haplogroup X was found to be prevalent among healthy aged people in the University of Miami study. _TechnologyReview

The second study, from UCLA researchers, looks at the ability of the brain to re-build following stroke -- or brain infarct. The team appears to have discovered a drug target with significant promise, which may lead to drugs that help the brain to re-build itself following destructive lesions.

A stroke is usually caused by a clot that blocks blood flow to an area of the brain. Tissue in that part of the brain dies from lack of oxygen unless the clot is detected immediately and is either dissolved or removed. The dead tissue cannot be revived, but often the brain can be trained to redirect nerve impulses via still-living nearby neurons. But such training is difficult, can require months to years of arduous rehab, and is often not sufficient to overcome complex disability.

The new research, by neurologist S. Thomas Carmichael and his colleagues at the University of California at Los Angeles, shows that neurons in the areas of the brain closest to the site of a stroke are impaired after it occurs. The reason for that is a buildup of an inhibitory signaling molecule called GABA that prevents the neurons from firing. When those nerves are inhibited, it's harder for the brain to recruit them into its rerouted circuits.

In studies in mice, the researchers discovered that blocking a particular piece of the GABA signaling system with an existing drug allowed the nerves to reactivate, reversing the repressed excitability, allowing them to more easily respond to other neurons, and encouraging and enhancing early recovery after a stroke by as much as 50 percent. "At face value, it's a new pharmacological target for repair and recovery in stroke," Carmichael says.

...Carmichael and his colleagues identified the piece of the GABA signaling cascade that goes awry in the area of the brain adjacent to the stroke: reduced levels of a transporter responsible for moving the inhibitory molecule out of the vicinity. Without that transporter, GABA is allowed to reach such high levels that the nearby neurons are prevented from firing.

In studies in mice, the researchers induced a stroke in the motor cortex, the movement center of the brain, and then gave them a drug that specifically reverses the post-stroke GABA uptake. The drug is not approved for use in people—it was an experimental molecule produced during the drug industry's search for memory enhancers. But just the fact that it works in mice means that stroke researchers have a new line of evidence to pursue.

"It's significant, because they're identifying a molecular mechanism that is keeping stroke survivors from recovering. And as a result, [Carmichael is] identifying targets for molecular manipulation," says Theresa Jones, a neurobiologist at the University of Texas at Austin. "Now we have potential to find drugs that aim at that target."

The scientists found that, as with other types of stroke treatments, timing was critical. During the first few days after a stroke, a brain injury is still stabilizing; prior studies have shown that any physical rehabilitation attempted during this period can aggravate the brain and actually make the damage worse. The same proved true for the drug.

But when the mice were given the drug three days later, it improved their recovery of movement by 40 to 50 percent. This implies that while the post-stroke inhibition of neurons in these areas may help with immediate recovery, but it is a harmful adaptation when it persists for weeks or months or even years after the initial injury. _TechnologyReview

Stroke is one of the major causes of death and disability in the developed world. A viable treatment for stroke rehabilitation would be a significant medical development.